The S6 kinase gene in the fruit fly, Drosophila melanogaster, is essential for metabolic regulation

Abstract

The S6 kinase (S6K) enzyme phosphorylates the S6 ribosomal protein, promoting protein translation and growth. Here we investigated in flies whether hypomorphic conditions in S6K affect intermediate metabolism and oxidative homeostasis, besides carbohydrates and growth. We also employed partial activation of the nuclear factor 2 erythroid related factor 2 (Nrf2) in a S6K hypomorphic background and controls. S6K is activated by the target of rapamycin (TOR) kinase, a key kinase regulating metabolism, downstream of the insulin receptor in flies. The insulin pathway is a general anabolic pathway, and key regulator of glucose homeostasis. The Nrf2 counters pro-oxidative conditions, also involved in inflammatory responses and metabolism. The Nrf2 fly homolog is Cap’n’collar C (CncC). We quantified glucose, glycogen, and total lipids in control and different pro-oxidative conditions. We corroborated an accumulation of lipids and carbohydrates in the mutants, and document sexual differences. We document also metabolic and survival differences in the responses to “mild” pro-oxidative conditions in young flies (seven days old), with females being most affected. We compare 10 mM paraquat survival of virgin flies to mated mixed-sex flies housed together. We used females to study transcriptomic differences between wild type and S6k hypomorphs. Results highlight dysregulation of lipid and antioxidant enzymes and genes, in agreement with lipid and oxidative metabolism data. Our results are consistent with the insulin/TOR pathway acting as an integrator of intermediate metabolism and oxidative homeostasis (this last together with the CncC pathway).